Ulipristal Acetate Tablets

ABSTRACT

The invention relates to a pharmaceutical tablet for oral administration comprising ulipristal acetate together with the following excipients: at least one diluent in an amount of 50 to 98.5 wt %, at least one binding agent in an amount of 0 to 10 wt %, at least one disintegrating agent in an amount of 0.5 to 10 wt %, and at least one lubricant in an amount of 0 to 10 wt %.

This application is a continuation of U.S. Ser. No. 13/140,219, filedDec. 7, 2011, which is a 371 of International Application No.PCT/EP2009/066652, filed Dec. 8, 2009 which is a continuation in part ofU.S. Ser. No. 12/329,865, filed Dec. 8, 2008, now U.S. Pat. No.8,512,745.

The present invention relates to a ulipristal acetate tablet for oraladministration, as well as to the manufacture and uses thereof.

BACKGROUND TO THE INVENTION

Ulipristal acetate, formerly known as CDB-2914, designates within thecontext of this application17α-acetoxy-11β-[4-N,N-dimethylamino-phenyl)-19-norpregna-4,9-diene-3,20-dione,represented by formula I:

Ulipristal acetate, and methods for its preparation, are described e.g.,in U.S. Pat. Nos. 4,954,490; 5,073,548, and 5,929,262, as well as ininternational patent applications WO2004/065405 and WO2004/078709.

Ulipristal acetate possesses antiprogestational and antiglucocorticoidalactivity, and has been proposed for contraception, in particular foremergency contraception, and for the therapy of various hormonaldiseases. Properties of this compound are further described in Blithe etal, Steroids. 2003 68(10-13):1013-7. So far, clinical trials have beenconducted using oral capsules of ulipristal acetate (Creinin et al,Obstetrics & Gynecology 2006; 108:1089-1097; Levens et al, ObstetGynecol. 2008, 111(5):1129-36). In order to increase the properties andclinical benefit of this molecule, there is a need for improvedformulations thereof.

SUMMARY OF THE INVENTION

The present invention relates to novel formulations of ulipristalacetate. More specifically, the invention relates to particular oraltablets of micronized ulipristal acetate. The inventors have now shownthat the bioavailability, and hence the efficiency of ulipristalacetate, can be enhanced when formulating ulipristal acetate as a tabletunder particular conditions. More specifically, the inventors haveconducted many tests and discovered that the properties of ulipristalacetate can be improved when this compound is formulated as an oraltablet using particular types and amounts of excipients.

Accordingly, the invention relates to a pharmaceutical tablet for oraladministration, comprising ulipristal acetate in an amount of 1 to 18 wt%, together with the following excipients: a diluent in an amount of 50to 98.5 wt %, a binding agent in an amount of 0 to 10 wt %, adisintegrating agent in an amount of 0.5 to 10 wt %, and a lubricant inan amount of 0 to 10 wt %.

In a preferred embodiment, the invention relates to a pharmaceuticaltablet for oral administration, comprising ulipristal acetate in anamount of 3 to 18 wt %, together with the following excipients: adiluent in an amount of 60 to 95 wt %, a binding agent in an amount of 0to 10 wt %, a disintegrating agent in an amount of 1 to 10 wt %, and alubricant in an amount of 0 to 5 wt %.

In another preferred embodiment, the invention relates to apharmaceutical tablet for oral administration, comprising ulipristalacetate in an amount of 3 to 18 wt %, together with the followingexcipients: a diluent in a total amount of 60 to 95 wt %, croscarmellosesodium in an amount of 1 to 10 wt %, and a lubricant in a total amountof 0 to 5 wt %.

In a yet preferred embodiment, the invention relates to a pharmaceuticaltablet for oral administration, comprising ulipristal acetate in anamount of 3 to 18 wt %, together with the following excipients: adiluent in an amount of 60 to 95 wt %, a binding agent in an amount of 0to 10 wt % (preferably 1 to 10 wt %), croscarmellose sodium in an amountof 1 to 10 wt %, and magnesium stearate in an amount of 0 to 5 wt %.

Surprisingly, the inventors have shown that a micronized ulipristalacetate formulation according to the present invention exhibits not onlyvery good pharmacotechnical characteristics (in particular hardness,friability, stability) for the manufacturing of the tablet, but alsoprovides a substantially improved dissolution profile for ulipristalacetate.

According to preferred embodiments, the formulation comprises 10% wtulipristal acetate and is designed to contain from 5 to 50 mg ulipristalacetate.

A further object of this invention relates to a method of manufacturinga ulipristal acetate tablet, the method comprising mixing the aboveingredients and ulipristal acetate and forming a tablet.

A further object of this invention resides in a method of contraceptioncomprising administering to a subject in need thereof an effectiveamount of a tablet of this invention.

A further object of this invention is a ulipristal acetate tablet asdefined above as a contraceptive.

A preferred object of this invention is a ulipristal acetate tablet asdefined above, for emergency contraception.

A further object of this invention resides in a method of treating ahormonal disease, such as uterine leiomyoma, comprising administering toa subject in need thereof an effective amount of a tablet of thisinvention.

A further object of this invention is a ulipristal acetate tablet asdefined above as a drug for treating a hormonal disease

LEGEND TO THE FIGURES

FIG. 1. Mean (±S.D) plasma concentration versus time profiles ofulipristal acetate on linear and log-linear scale. Comparison of thecollected data from the tablet comprising 10 mg ulipristal acetateversus the capsule containing 10 mg ulipristal acetate in 120 mgmicrocristalline cellulose.

X-axis: time in hours

Y-axis: Concentration of ulipristal acetate measured in the plasma inng/mL.

The concentration of ulipristal acetate was measured using liquidchromatography with tandem mass spectrometric detection LC-MS/MS, with avalidated calibration range in between 0.100-20.0 ng/mL. The sample waslater re-assayed using the non specific radioimmunoassay RIA BioqualInc.

FIG. 2. Dissolution profile of a tablet comprising 30 mg ulipristalacetate, with the following excipients: lactose monohydrate 79 wt %,povidone 5 wt %, croscarmellose sodium 5 wt % and magnesium stearate 1wt %.

X-axis: time in minutes

Y-axis: % dissolved composition

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel formulations of ulipristalacetate having improved properties. As disclosed above, the inventionrelates to oral tablets comprising ulipristal acetate combined withparticular types and amounts of excipients, namely:

-   -   a diluent,    -   optionally a binding agent,    -   a disintegrating agent, and    -   a lubricant.

The term <<a diluent>> means that one diluent or a mixture of severaldiluents may be used. Similarly, the term <<a disintegrant>> means thatone disintegrant or a mixture of several disintegrants may be used. Theterm <<a binding agent>> means that one binding agent or a mixture ofseveral binding agents may be used. The term “a lubricant” means thatone lubricant or a mixture of several lubricants may be used. Unlessotherwise specified, the term “a diluent in an amount of” is thereforesynonym to “at least one diluent in a total amount of”. The term “adisintegrant in an amount of” is therefore synonym to “at least onedisintegrant in a total amount of”. The term “a binding agent in anamount of” is therefore synonym to “at least one binding agents in atotal amount of”. The term “a lubricant in an amount of” is thereforesynonym to “at least one lubricant in a total amount of”.

As illustrated in the experimental section, the selected excipientsallow obtaining of granules having good processing properties(compressibility, flowability) and tablets with improvedpharmacotechnical properties: good hardness range, low friability andrapid disintegration.

Proportions of Ingredients:

The tablets of this invention comprise:

-   -   ulipristal acetate in an amount of 3 to 18 wt %, preferably 5 to        15 wt %, even more preferably 8-12 wt %, together with the        following excipients:    -   a diluent in an amount of 50 to 98.5 wt %, preferably 60 to 95        wt %, more preferably 65 to 92 wt %, yet even more preferably        70-85 wt %;    -   a binding agent in an amount of 0 to 10 wt %, preferably 1 to 10        wt %, more preferably 1.5 to 8.5 wt %,    -   a disintegrating agent, such as e.g. croscarmellose sodium, in        an amount of 0.5 to 10 wt %, preferably 1 to 10 wt %, more        preferably 1.5 to 8.5 wt %, and    -   a lubricant, such as e.g. magnesium stearate, in an amount of 0        to 5 wt %, preferably 0.5 to 4 wt %.

The term ‘wt %’ denotes an amount by weight, as a percentage of thetotal weight of the composition. The total percentage of the ingredientsin a tablet adds up to 100.

In a preferred embodiment, the composition comprises from 5-15 wt % ofulipristal acetate, even more preferably from 8-12 wt %, more preferablyabout 10 wt %.

A preferred composition of this invention comprises:

-   -   ulipristal acetate in an amount of 5-15 wt %; preferably 8-12 wt        %, more preferably about 10%,    -   a diluent in an amount of 65 to 92 wt %,    -   a binding agent in an amount of 0 to 10 wt %, preferably 1 to 10        wt %,    -   croscarmellose sodium in an amount of 1 to 10 wt %, and    -   magnesium stearate in an amount of 0.5 to 5 wt %, the total of        the percentage of the above ingredients in the tablet being 100.

In specific embodiments, ulipristal acetate is used in a dosage of 1 to50 mg per tablet, preferably 5 to 30 mg, particularly 10 or 30 mg.

As disclosed in the experimental section, these relative amounts lead totablets that are adapted to provide improved properties for ulipristalacetate. In particular, the results presented show that the use of atablet vs a capsule improves bioavailability, and that the particularratios of excipients and micronization as defined in the claims improvesthe dissolution profile.

Diluents:

The diluents may be selected from any pharmaceutically acceptable agentsor combinations of agents that increase the bulk quantity of ulipristalacetate so that production of a compressed tablet of practical size ispossible.

In a preferred embodiment, the diluent(s) is(are) selected from thegroup consisting of appropriate salts, monosaccharides, disaccharides,derivative polyols of monosaccharides and hydrates thereof. The term‘derivative polyols of monosaccharides’ stands for sugar alcohols suchas mannitol, xylitol or sorbitol.

Preferably the diluent(s) is(are) selected from the group consisting ofcalcium phosphate, sodium phosphate, calcium carbonate, sodiumcarbonate, cellulose, microcrystalline cellulose, lactose monohydrateand mannitol. For instance, studies were conducted by applicant toevaluate the effect of several distinct diluents on the tablet.Different batches were tested to assess the relative efficiency of thediluents. After addition of croscarmellose 5 wt % and magnesium stearate1 wt %, compositions with lactose monohydrate or mannitol, 70 to 85 wt%, led to tablets with excellent appearance, compression and flowabilityproperties.

Yet preferably, the diluent(s) is(are) selected from lactosemonohydrate, microcrystalline cellulose, and mannitol.

In a most preferred embodiment, the diluent is lactose monohydrate is anamount of 65 to 92 wt %, more preferably 70-85 wt %.

Preferably the ratio of diluents:other excipients (wt %:wt %) rangesfrom about 5 to about 25, preferably from about 7 to about 18, yetpreferably from about 7 to about 12.

Preferably the ratio of diluents:ulipristal acetate (wt %:wt %) rangesfrom about 5 to about 40.

When a binding agent is present in the tablet, the ratio ofdiluents:binding agents (wt %:wt %) preferably ranges from about 10 toabout 20.

Preferably the ratio of diluents:disintegrating agents (wt %:wt %)ranges from about 10 to about 80

Preferably the ratio of diluents:lubricants (wt %:wt %) ranges fromabout 20 to about 90.

Binding Agents:

When present, the binding agents, or binders, may be selected from anypharmaceutically acceptable agents (or combinations of agents) whichimpart cohesive qualities to powdered materials. The binding agents maybe selected from starch, gelatin, sugars such as cellulose derivatives(including hydroxypropyl methyl cellulose), and natural and syntheticgums (e.g., alginates) may be used.

Advantageously, a binding agent of the tablet according to the inventionis selected from the group consisting of polymers. The binding agent maybe a natural polymer material such as polysaccharide, or a syntheticpolymer such as a plastic polymer. Preferably, the binding agent ishydroxypropyl methyl cellulose and/or povidone.

For example, different tablets comprising 1 to 20 wt % of differentbinding agents (e.g., povidone, hydroxypropyl methyl cellulose or maizestarch) were manufactured by wet granulation as described below. Basedon these tests, a relative amount of 1-10 wt % binding agent wasretained as certain granules obtained with other amounts could not standthe drying step (formation of powder) and/or had lower dissolutionprofiles. Povidone or hydroxypropyl methyl cellulose gave the bestresults in that they enabled to obtain granules whatever diluents used(lactose monohydrate or mannitol at 70 to 85 wt %). Povidone isparticularly preferred since very hard and homogeneous granules wereobtained with povidone, which could easily stand the drying step.

Accordingly, in a preferred embodiment, the binding agent is orcomprises povidone, preferably 1.5% to 8.5 wt % of povidone, even morepreferably between 3-7 wt %, most preferably about 5 wt % povidone.

Preferably the ratio of binding agents:other excipients (wt %:wt %)ranges from about 0.025 to about 0.075.

Preferably the ratio of binding agents:ulipristal acetate (wt %:wt %)ranges from about 0.25 to about 0.75.

Preferably the ratio of binding agents:disintegrating agents (wt %:wt %)ranges from about 0.5 to about 1.5.

Preferably the ratio of binding agents:lubricants (wt %:wt %) rangesfrom about 3 to about 7.

Disintegrating Agents:

The present tablets comprise at least one disintegrant which, e.g.,facilitates break-up of the tablet.

Disintegrating agents may be selected from maize starch, alginic acidand croscarmellose sodium. For example, croscarmellose sodium may beused alone or in combination with other disintegrants, preferably alone.

The experiments performed by applicant have shown that croscarmellosesodium, when used in combination with the other ingredients of thepresent invention, allows to reduce the disintegration time and to keepgood pharmacotechnical characteristics when present in an amount of 0.5to 10 wt/%, preferably 1 to 10 wt/%, yet preferably 1.5 to 8.5 wt %, andmore preferably 4.5 to 5.5 wt %, or even more preferably about 5 wt %.

Preferably the ratio of disintegrating agents:other excipients (wt %:wt%) ranges from about 0.005 to about 0.1.

Preferably the ratio of disintegrating agents:ulipristal acetate (wt%:wt %) ranges from about 0.25 to about 0.75.

Preferably the ratio of disintegrating agents:lubricants (wt %:wt %)ranges from about 0.5 to about 7.

Lubricants:

The present tablets comprise one or more lubricants.

Lubricants may be selected from stearic acid, talc and magnesiumstearate.

In preferred embodiments, the tablets of the present invention containat least magnesium stearate, and optionally talc. Indeed, the inventorshave shown that magnesium stearate is the most adapted lubricant toprevent adhesion to the tablet material to surfaces in the manufacturingprocess and to improve the flow characteristics of the powder materialduring manufacture of ulipristal acetate tablets.

Magnesium stearate may be used in combination with other lubricants oralone, in an amount comprised between 0.5 and 4 wt %.

Preferably the ratio of lubricants:other excipients (wt %:wt %) rangesfrom about 0.01 to about 0.06.

Preferably the ratio of lubricants:ulipristal acetate (wt %:wt %) rangesfrom about 0.1 to about 2

In a particular embodiment, the ratio of croscarmellose sodium:magnesiumstearate (wt %:wt %) ranges from about 0.75 to about 5, preferably about5, or from about 1 to about 2, more preferably about 1.5 or 1.7.

Preferred Embodiments

Preferably, the tablet according to the present invention compriseslactose monohydrate as a diluent and povidone as a binding agent.

Alternatively, the tablet according to the present invention comprisesmannitol and cellulose (such as microcrystalline cellulose) as diluentsand does not contain any binding agent.

In a more specific embodiment, the tablet comprises: ulipristal acetate5 to 15 wt %, lactose monohydrate 71 to 87 wt %, povidone 4.5 to 5.5 wt%, croscarmellose sodium 4.5 to 5.5 wt % and magnesium stearate 1 to 4wt %, where the total percentage adds up to 100.

In an even more specific embodiment, the tablet comprises: ulipristalacetate 10%, lactose monohydrate 79 wt %, povidone 5 wt %,croscarmellose sodium 5 wt % and magnesium stearate 1 wt %.

In yet another specific embodiment, the tablet comprises: ulipristalacetate about 10 mg (6.7 wt %), microcrystalline cellulose about 91 mg(61 wt %), mannitol about 41 mg (27 wt %), croscarmellose sodium about2.5 mg (1.7 wt %), talc about 4 mg (2.6 wt %) and magnesium stearateabout 1.5 mg (1 wt %), where the total percentage adds up to 100.

The tablets can be prepared at a dosage of e.g., 5, 10, 15, 20 or 30 mgulipristal acetate.

Tabletting:

Tablets of the present invention may be prepared according to techniquesknown per se in the art. Suitable methods include direct compression(“dry blending”), dry granulation followed by compression, and wetgranulation followed by drying and compression. Several methods includethe use of compacting roller technology such as a chilsonator or droproller, or molding, casting, or extrusion technologies. All of thesemethods are known per se in the art, and are described in detail in, forexample, Lachman, et al., “The Theory and Practice of IndustrialPharmacy,” Chapter 11, (3.sup.rd Ed. 1986), which is incorporated byreference herein. The tablet according to the invention can be coated ornot, and/or engraved or not.

A preferred method for producing tablets of this invention is a wetgranulation process. Indeed, the inventors have shown that such a methodimproves the qualities of the powder before compression and reduces thesize of the tablet. More particularly, the wet granulation process ledto better pharmacotechnical results on blends, an improvement ofcompressibility characteristics and a decrease of the final tablet mass.

An object of the present invention therefore resides in a method ofmanufacturing an ulipristal acetate tablet, the method comprising mixingthe above ingredients and ulipristal acetate and forming a tablet. In apreferred embodiment, the tablet is formed by wet granulation,especially when 10 to 30 mg ulipristal acetate tablets, more preferably30 mg ulipristal acetate tablets are prepared.

The ingredients may be all mixed together simultaneously, orsequentially. In a typical embodiment, the diluent (e.g., lactosemonohydrate), ulipristal acetate and the binding agent (e.g., povidone)are first mixed together, followed by addition of purified water. Thisgranulation step is then followed by a drying step (e.g., in an oven atabout 40° C., or on a fluidized air bed, or in a one-pot granulator).Optionally, a calibration step is then carried out, e.g., with a sievecomprised between about 600 and 850 μm, such as a 800 μm sieve or a 710μM Frewitt sieve. Croscarmellose sodium and magnesium stearate are thenadded for the lubrication. The obtained formulation is then compressedto get the tablet (compression step). As a result of this process,croscarmellose (which is added after the granulation step) is in theexternal phase of the tablet, thereby allowing better disintegration anddissolution.

In the preparation of the tablets of this invention, commercial mixturescomprising diluents and binding agents may be used, such as Avicel®(microcristalline cellulose), Starlac® (lactose monohydrate 85% withmaize starch 15%) or, Ludipress® (lactose monohydrate 93% with Povidone7%).

In another embodiment, the tablet is formed by direct compression,especially when 5 or 10 mg ulipristal acetate tablets are prepared. Whendirect compression is conducted, the presence of a binding agent may beavoided.

An example of a direct compression method includes a blanketing step(e.g., with mannitol), then a premix step by adding ulipristal, followedby sieving, and mixing once microcrystalline cellulose andcroscarmellose sodium have been added. Then comes a lubricating step byadding the other excipients (e.g., talc and magnesium stearate) beforetableting. The skilled person in the art may of course adapt such stepsto obtain the desired tablets.

Therapeutic Applications:

The ulipristal acetate tablets of the invention are useful in a numberof therapeutic indications, including contraception, including emergencycontraception.

The tablets of the invention are useful in other indications including,but being not limited to, endometriosis, dysmenorrhea, uterine leiomyoma(leiomyomata), uterine fibroid, excessive uterine bleeding(menorrhagia), either idiopathic or resulting from spontaneous oriatrogenic coagulation disorders, meningioma, hormonal diseases, such ashormone-responsive cancers, endocrine hormone-dependent tumors, breastcancer and inhibition of uterine endometrial proliferation.

It is further contemplated to provide similar formulations for otherantiprogestins, such as those described in international patentapplications WO2008/083192 or WO2008/067086.

Further aspects and advantages of the present invention will bedisclosed in the following examples, which should be considered asillustrative and not limiting the scope of the present application.

EXAMPLES Example 1 30 mg Ulipristal Acetate Tablet Produced by WetGranulation

A 30 mg ulipristal acetate tablet was prepared, containing the followingingredients:

TABLE 1 Quantity for one Quantity for one Ingredients tablet (mg) tablet(wt %) Ulipristal acetate 30.00 10 Lactose Monohydrate 237.00 79Povidone 15.00 5 Croscarmellose 15.00 5 sodium Magnesium stearate 3.00 1Total 300.00 100

Lactose monohydrate 79 wt %, ulipristal acetate 10 wt % and povidone 5wt % were mixed and purified water was added. This granulation step wasimmediately followed by a drying step in an oven at 40° C. Then, acalibration step with a Frewitt 630 μm sieve was carried out.Croscarmellose sodium 5 wt % and magnesium stearate 1 wt % were addedfor the lubrication step. The obtained formulation is compressed to getthe tablet.

Example 2 Other Ulipristal Acetate Tablets Produced by Wet Granulation

Further compositions of this invention contain the followingingredients:

TABLE 2 10 mg tablet 30 mg tablet Quantity for one Quantity for oneIngredients tablet in mg (wt %) tablet in mg (wt %) Ulipristal acetate10.00 (10) 30.00 (10) Lactose Monohydrate 79.00 (79) 246.00 (82) Povidone 5.00 (5) 9.00 (3) Croscarmellose sodium 5.00 (5) 12.00 (4) Magnesium stearate 1.00 (1) 3.00 (1) Total 100.00 (100) 300.00 (100)

Example 3 10 Mg Ulipristal Acetate Tablet Produced by Direct Compression

A 10 mg ulipristal acetate tablet was prepared containing the followingingredients:

TABLE 3 Quantity for Quantity for one Ingredients one tablet (mg) tablet(wt %) Ulipristal acetate 10.00 6.7 Mannitol 41.00 27 Microcrystalline91.00 61 cellulose Croscarmellose sodium 2.5 1.7 Magnesium stearate 1.51 Talc 4.0 2.6 Total 150.00 100

This tablet was produced by mixing mannitol and ulipristal acetate, thensieving, e.g. with a 315 μm mesh size, and adding microcrystallinecellulose and croscarmellose sodium. Talc and magnesium stearate werethen added to the mixture as lubricants, and homogeneized. Tablettingwas achieved by direct compression of the mixture. Quantities ofexcipients may be adapted (for example halved or doubled) whileremaining in the same proportions in wt %. Tablets with a total weightof 75, 150, 300 mg, containing 10 mg ulipristal acetate, and the sameexcipients as recited in Table 3 can be prepared accordingly

Example 4 Bioavailability Studies

A comparative bioavailability study of a 10 mg tablet (as preparedaccording to example 3) vs different ulipristal acetate capsuleformulations and a study characterizing the pharmacokinetic profile havebeen performed. Various assay methods have been employed in themeasurement of ulipristal acetate in plasma or serum, includingradioimmunoassay (RIA) and liquid chromatography with tandem massspectrometry (LC-MS/MS). Because of the presence of cross-reactingmetabolites, the RIA fails to distinguish the parent ulipristal acetatefrom potential cross-reactive metabolites present in the circulation,and results reported using this method hence represents the sum ofulipristal acetate and its cross-reactive metabolites. The LC-MS/MS hasbeen developed for use in menopausal and non menopausal human plasma andserum, and permits separation and determination of both ulipristalacetate and its pharmacologically active metabolite,17α-acetoxy-11β-[4-N-methylamino-phenyl)-19-norpregna-4,9-diene-3,20-dione.

The comparative bioavailability study also included a re-assay ofsamples using the non-selective RIA, thereby providing a point ofreference to which results from other studies could be comparedirrespective of the analytical method employed.

Comparative bioavailability studies were performed as a pharmacokineticbridging study between different formulations of ulipristal acetate. Theformulations tested included a 10 mg capsule with micronized ulipristalacetate in 120 mg microcrystalline cellulose, and a 10 mg ulipristalacetate tablet. The experiments were carried out to compare thebioavailability and the bioequivalence of ulipristal acetate, or of itsmetabolites, between these two formulations. As disclosed in Table 4below, the best absorption profile was observed for the tabletformulation with the following PK parameters (mean±SD or range): Cmax:56.7±29.1 ng/mL, tmax: 0.63 h (mean range: 0.50-2.00 h), AUC_(0-t):171.79±85.59 h·ng/mL.

The term ‘C_(max)’ stands for a peak of ulipristal acetate concentrationin the plasma. The term ‘AUC_(0-t)’ denotes the area under theconcentration time profile from 0 to time t. The term ‘SD’ refers tostandard deviation.

TABLE 4 Ulipristal C_(max) AUC_(0-t) AUC_(0-∞) acetate 10 mg T_(max) (h)(ng/ml) (ng · h/ml) (ng · h/ml) Capsule Mean 1.13⁽¹⁾ 35.0 170.58 193.37Range 0.5-3.00 15.0-64.1 53.4-291.9 62.9-315.4 SD — 20.0 84.18 96.93 CV(%) 60 57 49 50 Tablet Mean 0.63⁽¹⁾ 56.7 171.79 189.86 Range 0.50-2.0020.7-94.5 74.3-291.7 85.7-340.7 SD — 29.1 85.59 99.90 CV (%) 63 51 50 53⁽¹⁾Median

The results from comparative bioavailability studies also suggest thatulipristal acetate is absorbed faster and has a greater overallbioavailability for tablet compared with the capsule. Mean C_(max) andAUC_(0-t) for ulipristal acetate was in the best cases 95% and 40%higher, respectively, after administration of the tablet compared to thecapsule (see FIG. 1). This trend was also reflected in a mean C_(max)and AUC_(0-t) for the active monodemethylated metabolite,17α-acetoxy-11β-[4-N-methylamino-phenyl)-19-norpregna-4,9-diene-3,20-dione,that was 92% and 25% higher, respectively, for the tablet versus thecapsule.

The lipids or surfactants that are present in the capsule compositionare expected to help to achieve an immediate dissolution of thecompound, and to make it easier to be absorbed in both the stomach andintestine, with a preference for the intestine, i.e. the lower GIT(Gastro-Intestinal Tract). However, the results obtained by theinventors surprisingly show that, in comparison with the capsuleformulation, the tablet formulation was absorbed faster, had a higherplasma concentration peak, and had a greater overall bioavailability asmeasured by the AUC measured in the study and extrapolated to infinityfor the parent compound and metabolite.

These pharmacokinetic results demonstrate the advantages of the tabletform versus the capsule.

Example 5 Dissolution Profile for the Tablet According to Example 1

Dissolution studies were carried out using various tablets, includingthe tablet of example 1. The dissolution tests were conducted accordingto the general monograph of the European Pharmacopoeia §2.9.3:

-   -   Paddle apparatus    -   Dissolution medium: HCl 0.1N    -   Rotation speed: 50 rpm    -   Temperature: 37° C.±0.5° C.

The results depicted in FIG. 2 show that the tablets of this inventiondissolve fully and rapidly.

Example 6 Comparative Dissolution Profiles

Table 5 presents the comparative dissolution profiles of the tablets ofexamples 1 and 3, which contain different ratios of ingredients. Theresults unexpectedly show that the tablet of Example 1 has a much betterdissolution profile than the tablet of example 3, illustrating theimportance of the specific excipients and ratios for ulipristal acetateformulations.

TABLE 5 Comparative dissolution profiles: ulipristal acetate dissolved(%) versus time (minutes) Time (min) 0 5 10 20 30 45 60 formulation 0 8091 95 94 94 96 of Table 1 (Example 1) formulation 0 71 83 89 91 93 93 ofTable 3 (Example 3)

1. An oral pharmaceutical tablet comprising ulipristal acetate in anamount ranging from 1 mg to 50 mg, a diluent, a disintegrating agent,and a lubricant, wherein at least 80% of ulipristal acetate present inthe tablet is dissolved within about 20 minutes when said tablet issubjected to an in vitro dissolution assay in a paddle apparatus at 37°C.±0.5° C., and at pH=1.
 2. The tablet of claim 1, wherein at least 90%of ulipristal acetate present in the tablet is dissolved within about 20minutes when the said tablet is subjected to an in vitro dissolutionassay in a paddle apparatus at 37° C.±0.5° C., a rotation speed of 50rpm, and at pH=1.
 3. The tablet of claim 1, wherein the disintegratingagent is sodium croscarmellose.
 4. The tablet of claim 1, which furthercomprises a binder.
 5. The tablet of claim 4, wherein the binder is asynthetic or natural polymer.
 6. The tablet of claim 5 wherein thebinder is povidone and/or hydroxypropyl methyl cellulose.
 7. The tabletof claim 1, wherein the diluent is selected from the group consisting ofmonosaccharides, disaccharides, calcium phosphate, sodium phosphate,calcium carbonate, sodium carbonate, cellulose, microcrystallinecellulose, combinations and hydrates thereof.
 8. The tablet of claim 7,wherein the diluent is selected from the group consisting of mannitol,lactose, microcrystalline cellulose, hydrates thereof and combinationsthereof.
 9. The tablet of claim 1, wherein the lubricant is selectedfrom the group consisting of steraic acid, talc, magnesium stearate andcombinations thereof.
 10. The tablet of claim 1, which comprises: from1% to 18% by weight of ulipristal acetate, from 50% to 98.5% by weightof a diluent, from 0.5% to 10% by weight of a disintegrating agent, andfrom 0% to 10% of a lubricant.
 11. The diluent of claim 10 wherein thediluent is in an amount of 65 to 92 wt %.
 12. The tablet of claim 10,wherein the binding agent is in an amount of 1.5 to 8.5 wt %.
 13. Thetablet of claim 10, wherein the disintegrating agent is in an amount of1.5 to 8.5 wt %.
 14. The tablet of claim 10, wherein the lubricant is inan amount of 0.5 to 5 wt %.
 15. The tablet of claim 10, comprising from5 to 30 mg of ulipristal acetate.
 16. The tablet of claim 1, which isuncoated.
 17. The tablet of claim 1, wherein ulipristal acetate ismicronized.
 18. A method of manufacturing an oral ulipristal acetatetablet of claim 1, the method comprising the step of mixing theingredients and ulipristal acetate and forming a tablet, preferably bywet granulation or by direct compression.